Antiviral medications Lecture 9

Question 1

General concepts and 5 major categories antiviral medications are used for clinical treatment

Answer 1

viruses are obligate intracellular parasites composed of either DNA or RNA wrapped in a protein nucleocapsid

herpes family viruses: varicella (chicken pox), Zoster (shingles), encephalitis, oral and genital

cytomegalovirus: transplant patients, AIDS/ immunosuppressed patients

Influenza: Types A and B (majority A)

Respiratory syncytial virus: RSV bronchiolitis in children

HIV: systemic destruction of helper t cells

Question 2

Goal of antiviral therapy

Answer 2

to inhibit or eliminate teh activity of a virus with minimal effect on host function

Target therapy include: interference of attachment to the host cell membrane and entry into the host cell. Inhibiting the process of transcription or translation. Interference of viral assembly.

Question 3

Acyclovir MoA

Answer 3

after uptake by an infected cell, acyclovir is phosphorylated to the inactive monophosphate form by a virus specific thymidine kinase and the to the activated triphosphate form my cellular enzymes. The triphosphate form then inhibits viral DNA polymerases and competes with deoxyguanosine triphosphate. This triphosphate lacks the 3 hydroxyl group necessary for insertion of the next nucleotide int he growing DNA chain thus acts as a chain terminator.

Question 4

Acyclovir Pharmacokinetics

Answer 4

Renal elimination (60-90%)= adjustment required

bioavailability= 10-30%

Half life = 2-20 hours (renal function dependent)

Good CSF penetration

Excellent placenta and umbilical cord penetration

Question 5

Acyclovir AE

Answer 5

Well tolerated by most patients

the intravenous formulation can result in phlebitis or in inflammation at the site of infusion

reversible renal toxicity due to crystalline nephropathy occurs in 5-10% of patient receiving the IV formulation (more common with high douse bolus infusions).

GI (N,V,D- likely dose of age dependent)

CNS (HA, Lethargy, tremors, hallucinations, and seizures)

hepatic (hyperbilirubinemia, jaundice, and hepatitis have been reported)

Question 6

Acyclovir Clinical use

Answer 6

best result if herapy is started within 72 hours of first lesion/rash for herpes

primary 10 days of tx episodes of genital herpes simplex

recurrent 5 days of tx episodes of genital herpes simplex

suppression of frequent recurrences (>6 times per year)

IV formulation for encephalitis (10mg/kg q8Hrs)

herpes zoster (toxicity resistance, and cost vs postherpetic neuralgia). Best results if used early in rash presentation

not effective for cytomegalovirus infections

Question 7

Valcylovir general and pharmacokinetics

Answer 7

prodrug of acyclovir- L valyl ester of acyclovir

Pharm: after absorption, valacyclovir is rapidly and virtually completely converted to acyclovir via first pass intestinal/epatic metabolism and hydrolysis

excellent bioavailabiltiy (~70%) produces similar levels to IV acyclovir.

Question 8

Valcyclovir AE and clinical use

Answer 8

high dose have been associated with confusion, hallucinations, nephrotoxicity, and uncommon but severe thrombocytopenia syndromes.

Clinical use: herpes zoster tx, HSV tx and suppression in immunocompetent patients, recurrent herpes simplex suppression in HIV infected patients. Advantages over acyclovir: less frequent dosing (BID vs TID 5x a day)

Question 9

Ganiciclovir Description and MoA

Answer 9

acyclic nucleoside analogues of guanine similar to acyclovir

MoA: Metabolized by thymidine kinase and other enzymes to triphosphate analog which inhibits DNA polymerase and incorporates into viral DNA. Preferntially phosphorylated to active drug in CMV infected mammalian cells.

Question 10

Ganicyclovir Pharmocokinetics

Answer 10

In virtor, ganiciclovir is at least 10 times more potent than acyclovir in the inhibiton of CMV and epstein barr and equal to acyclovir for herpes simplex and varicella zoster.

oral bioavalability= 6-9%

Question 11

Ganciclovir AE and clinical use

Answer 11

Bone marrow suppression- mainly neutropenia and to a lesser degree thrombocytopenia and anemia. Bone marrow suppression in usually reversible with dosage reduction/therapy discontinuation and seems to be more common in patients with AIDS over solid organ transplant patients

CNS (HA, behavioral change)

GI (nausea and vomiting)

Clinical uses: CMV retitinits TX. COMV prophylaxis in transplant patient and advanced HIV infections. PO formulation approved for prophylaxes therapy and after appropriate induction therapy with IV formulation. Other IV FDA indications inclue esophagitis, gastritis, and colitis. Intravitreal ganciclovir is a surgically implated devices exclusively for CMV retinits in atients with AIDS.

Question 12

Valganciclovir

Answer 12

Prodrug of ganiclovir

Bioavailibilty=60%. Increased with high fat meals. renally excreted requiring renal adjustment.

Question 13

Valganciclovir AE and clinical uses

Answer 13

Bone marrow suppression- mainly neutropenia and to a lesser degree thrombocytopenia and anemia. Bone marrow suppression in usually reversible with dosage reduction/therapy discontinuation and seems to be more common in patients with AIDS over solid organ transplant patients

CNS (HA, behavioral change)

GI (nausea and vomiting)

Clinical use: CMV retinitis, CMV prophylaxis

Question 14

Peniclovir: Pharmacokinetics and MoA

Answer 14

Acyclic guanine nucleoside analog

Pharmacokinetics: only available in the US as a 1% topical cream.

MoA: Similar to acyclovir. Viral thymidine kinase phosphyrlates penciclovir to monophosphate form which, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and there fore replication are selectively inhibited.

Question 15

Peniciclovir: AE and clinical uses

Answer 15

AE: application site irritation. HA?

Clinical use: HSV (cold sores) apply every 2 hours while awake for 4 days to potentially reduce healing time, viral shedding and pain.

Question 16

Famciclovir

Answer 16

Descrption Prodrug of penciclovir.

MoA: similar to acyclovir

Pharmacokinetics: Bioavailability= 65-77%. Renally excreted requiring dose reductions.

AE: CNS (HA), GI (N,V,D)

Clinical use: Herpes zoster (shingles) tx. Best results start with 72 hours of rash onset. HSV tx or suppression of immunocompotent patient. Recurrent mucocutaneous HSVS tx in HIV patients.

Question 17

Cidofovir MoA

Answer 17

speculated that cidofovir diphsosphate interacts with DNA polyemerase either as an alterantive substrate (incorporation at the 3’ end or within interior of DNA chain) or as a competitive inhibitor (with respect to the normal substrate dCTP)

it is unlike acyclovir or ganciclovir, phosphorylation of cidofovir to its active metabolite does not depend on virus specific thymidine kinase

Question 18

Cidofovir AE and CLinical use

Answer 18

AE: Highly nephrotoxic (avoid use in patients with SCr > 1.5 mg/dl or higher). Misc: neutropenia, ocular hypotony, and metabolic acidosis

Clinical uses: must be administred with probenecid and normal saline to decrease chances of nephrotoxicity. Dose 5 mg/kg once weekly for two weeks then every other week until progression of retinits or adverse affects. Reversed for CMV retiniits in AIDS patients who have failed or are intolerant to ganciclovir and foscarnet.

Question 19

Foscarnet MoA

Answer 19

MoA: competes for pyrophosate site in viral but not human DNA polyerase and revese transcrptase.

Foscarnet is an orgnic phosphate that does not require phosphorylation by thymidine kinase, thus remains effective against many strains

Question 20

Foscarnet AE:

Answer 20

Nephortoxic, electrolytes (severe electrolyte distrbances), CNS (seizures, fever), hematologic (anemia, neutropenia), GI (N/V/D), Cardiology (EKG changes, 1st degree AV block, hyper and hypotension.)

Question 21

Foscarnet clinical uses

Answer 21

second line agent due to high incidences of AE

CMV retinits in patients with AIDS (combo with ganciclovir in recurrence in superior)

acyclovir resistant mucocutaneous herpes simplex in immunosuppressed.

Question 22

Lamivudine description and MoA

Answer 22

Originally studied and marketed as an antiretroviral agent (HIV)

MoA: Metabolized intracellular to dideoxynucleotide triphosphate (DDATP) which inhibits reverse transcrptase and incorporates into viral DNA. Subsequent nucleotides fail to bind to ddATP becaues it lacs the necssary free 3 hydroxyl group, thus DNA chain termination.

Question 23

Lamivudine: AE and clinical use

Answer 23

AE: black box warning: lactic acidosis and severe heptaomegaly (fatty liver statosis). GI (diarrhea), CNS (HA, fatiuge insomnia, peripheral neurpathy), musculoskeletal arthralgias, dermatolgoic rash

Clinical use: Hep B virus. Make sure to rule out HIV infection first. HIV (more treatments options later).

Question 24

Ribavarin MoA and Pharmacokinetics

Answer 24

MoA: Unknown

Pharmacokinetics: bioavailibilty 50%. Food increases absorption substantially. Half life 200-300 hours at statdy state. Reneally eliminated use with caution to Cr Cl < 50 ml/min

Question 25

Ribavarin AE and clinical use

Answer 25

AE: anemia (dose related). Combination with interferon increases the risk of fatigue, rash, pruritius, depression, esp anemia which leads to a high precentage of discontinuation of treatment early.

CLinical uses: respiratory syncytial virus bronchiolitis and pneumonia in hospitalizzed children. Hep C (standard treatment in combination with intereron alpha 2a or 2b). Genotype 1 requires 48 weeks; genotype 2 and 3 rquires 24 weeks of therapy.

Question 26

Imiquimod

Answer 26

topical treatment of condylomata acuminate (genital warts)

induces local interferon alpha, beta, gamma, and TNF alpha > reduced viral load/wart size.

Apply 3 times a week for up to 16 weeks > complete clearance in 50% of patients

relapses are not uncommon after tx.

Question 27

Amantadine and rimantidine

Answer 27

MoA: prevents virus from entering susceptible cells

CNS AE are worse with amantadine compared to rimantidin (anxiety, nervousness, confusion, and insomnia.)

amantadine rrequires renal adjustment for renal dysfunction whereas rimatadine does not

both are used for prophylaxis adn treatment of influeza A

for treatment of influenza A, it is important to start therapy within the first 48 hours of symptoms.

amantadines’ ability to treat parkinsonism was discovered serendipitously

Question 28

Neuroamidase inhibitors Osteltamivir, Zanamivir

Answer 28

MoA: speicfic inhibitor of influenza virus neroaminidase which is required for release of the virus from infected cells leading to a reduction in spread of the virus

OSteltamivir AE: nausea, emesis, and abdominal discomfort most likely due to local irritation. These side effects typically resolve within 1-2 days are mild to moderate in nature and can be minimized by taking ostetamivir with food.

Zanamivir is an oral inhalation of dry powder typically well tolerated: however, reports of wheezing and bronchospasm in patinets without known airway disease have occurred. Use of zanamivir is discouraged in COPD and asthma patient due to the risk of seriious adverse events.

Both are effective for the prevention and treatment of both influenza A and B.